In this competing renewal, we propose to continue a 25-year investigation of the epidemiology of HIV risk among HIV-uninfected injection drug users (IDUs) enrolled in the AIDS Linked to the IntraVenous Experience (ALIVE-II) Study in Baltimore, MD. This study has provided critical insight into the dynamics of HIV infection and risk behavior while serving as a comparison group to a parallel cohort of HIV positive IDUs (DA04334, ALIVE-I). Our investigative team has been highly productive during the past funding cycle (105 publications & 77 major presentations) and, over the next five years, we will continue cutting-edge and innovative broad- based investigations, while serving as a resource for clinical and pathogenesis studies related to HIV and HCV infection. In this proposal, we present a focused effort related to hepatitis C virus (HCV), which represents the major challenge that IDUs will face over the next decade. HCV prevalence ranges from 50-90% in IDU populations and morbidity and mortality secondary to HCV infection is expected to dramatically increase over the next decade. Building on lessons learned from HIV, we focus on collecting information to evaluate the population-level effectiveness of current HCV 'Test-and-Treat' initiatives and provide insight to the development of new interventions to target HCV testing, linkage to care, treatment and Treatment as Prevention (HCV-TasP). Our Specific Aims are to: 1) Characterize the continuum of care for HCV among IDUs and its evolution over time with increasingly efficacious antiviral therapy; 2) Assess population-level effectiveness of hepatitis C treatment among IDUs in Baltimore; 3) Develop a mathematical model of HCV treatment dynamics to assess the potential impact and cost-effectiveness of different intervention strategies; and 4) continue to serve as an HIV negative comparison group for longitudinal investigation of non-AIDS outcomes and a platform for independently funded related studies. To achieve these aims, we will continue follow-up of a cohort of HIV negative IDUs (~1000) with semiannual visits and will open recruitment twice over the proposed funding period. New recruitment will occur in 2013-2014 and 2016-2017; 500 participants at each time point will be accrued via respondent-driven sampling. The ALIVE-II cohort is unique in that it comprises a community-based IDU population of both genders with significant representation of African-Americans and those with limited access to appropriate medical care; these populations have been underrepresented in research on persons at risk for HIV infection. We collaborate with ALIVE-I, a parallel cohort of HIV-infected IDUs that capitalizes on the same protocol, facilities and staff with no fiscal overlap. Given the scientific rigor of the proposed methods, existing infrastructure, experienced investigators and multiple NIH-funded ancillary studies, we anticipate continued success and substantial scientific contribution.